CD36 is a broadly expressed 88 kD transmembrane glycoprotein which functions as a scavenger receptor, adhesion and signaling molecule and a facilitator of fatty acid transport. Previous work by our group and others determined that CD36 was a major mediator of macrophage foam cell formation and atherogenesis. Recently, a paradox has emerged: significant protection against lesion development and progression was observed in experimental conditions where CD36 was rendered absent genetically and when CD36 was upregulated by pharmacological means. Using stem cell transfer of CD36/apoE bone marrow into apoE null animals, we found that the atheroprotective effect afforded by complete absence of CD36 was not fully realized. Thus, a major hypothesis of this application is that CD36 has atheroprotective properties independent of its role as a scavenger receptor. Based on emerging data, we focus on the role of CD36 in efflux pathways and in modulating insulin-resistance, both of which are stimulated by drugs which activate PPARs, transcription factors which regulate CD36 expression. We hypothesize that CD36 is a critical player in maintenance of vessel wall homeostasis, and that entry of cholesterol into macrophages via CD36 facilitates removal of pro-atherogenic modified LDL from the intima, and ultimately allows lipid clearance through efflux pathways. Elucidation of the regulation of CD36 in relationship to the major efflux pathways is a major goal of our studies. Insulin resistance is a separate risk factor for atherogenesis and results in its premature development. We hypothesize that a portion of the protective role of CD36 in atherogenesis is related to its effect on glucose and fatty acid metabolism. We will utilize unique animal models we have on hand to explore the differential impact of CD36 on atherosclerosis based on scavenger receptor function or its role as a facilitator of fatty acid transport and determinant of insulin sensitivity. These approaches will enable us to design more specific treatment regimens which will ultimately impact on human health and disease.